Dual-chamber carpule

ABSTRACT

The invention relates to a dual-chamber carpule having a first partial cylinder comprising a sealing cap, a bypass, and an intermediate stopper, an optional sealing element, and a second partial cylinder comprising an end stopper and, optionally, a stop, an axial groove, and an additional intermediate stopper; the invention further relates to a method for producing and filling said dual-chamber carpule.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/636,948 filed on Dec. 14, 2009, which is a continuation ofInternational Patent Application No. PCT/EP2008/004356 filed May 31,2008, which claims priority to European Patent Application No.07011686.8, filed Jun. 14, 2007. The entire disclosure contents of theseapplications are herewith incorporated by reference into the presentapplication.

FIELD OF INVENTION

Two-chamber carpules are used in medicine for administering preparationsthat comprise two components. There are two possibilities here forcombining the components, namely the liquid/liquid combination and thesolid/liquid combination. Two-chamber carpules have the advantage thatthe mixing of the two components can take place without decanting intoanother container and that administering can then be performed directlyfrom the container. Two-chamber carpules can be used in reusable syringeor pen systems intended for them.

BACKGROUND

DE 4445969, EP 718002 and US 5,778,670 describe syringe cylinders oftwo-chamber syringes for two components to be applied, a firstpart-cylinder, preferably the part-cylinder on the head side, containinga medicament to be lyophilized, and a second part-cylinder, preferablythe part-cylinder on the plunger side, containing a liquid component.During administering, the powdered medicament mixes with the liquidcomponent by way of a bypass. The part-cylinder on the needle sidecontains the bypass and is closed at the proximal end by a plug. Thepart-cylinder on the plunger side is closed at the proximal end on theplunger side (FIG. 2) by a plug and optionally at the distal end (FIG.3) by a further plug. The two part-cylinders are connected to each otherby means of material bonding (by welding) or by means of nonpositiveengagement (by adhesion). The syringe cylinders described have a bypass,which is preferably formed in such a way that it does not increase thediameter of the syringe cylinder. The material of the frontpart-cylinder is preferably plastic. In the method for filling thesyringe cylinder, the syringe head of the first part-cylinder is closedby a so-called tip cap, i.e. by a loose closure through which thesurrounding vacuum can be passed on to the interior of the syringecylinder in the freeze-drying that follows filling with a lyophilizate,and which is only securely closed after the freeze-drying step. Separatefilling into a first part-cylinder and a second part-cylinder avoidscross contamination and permits optimum utilization of the process spaceof the lyophilizer.

European patent application EP 520618 describes a prefilled syringecomprising two part-cylinders, the first part-cylinder, preferably thepart-cylinder on the head side, which comprises the needle or theoutlet, containing a lyophilized, powdered medicament, and the secondpart-cylinder, preferably the part-cylinder on the plunger side,containing a second, liquid component. During administering, thepowdered medicament mixes with the liquid component by way of a bypass.The part-cylinder on the needle side contains the bypass and is closedat the proximal end by a plug. The part-cylinder on the plunger side isclosed at the distal end and at the proximal end by a plug in each case.The two part-cylinders are separately sealed by means of the plugs andconnected to each other by means of flanges, the proximal plug of thepart-cylinder on the head side and the distal plug of the part-cylinderon the plunger side being positively connected to each other after beingjoined together, and the overall length of the two plugs being shorterthan the length of the bypass.

GB 2010681 describes a two-chamber syringe for administering a liquidcomprising two part-cylinders, the first part-cylinder being formed as aneedle holder and comprising a channel to the outlet, and the secondpart-cylinder, on the plunger side, containing liquid. The firstpart-cylinder does not contain any substance to be administered. Duringadministering, a plunger with which the part-cylinder on the plungerside is closed at the distal end is moved in the direction of thesyringe head, whereby the liquid can be applied by way of the channel ofthe first part-cylinder.

FR 1099362 describes a two-chamber syringe comprising twopart-cylinders, the first part-cylinder, on the head side, containing asterile powder or a sterile liquid and the second part-cylinder, on theplunger side, containing a liquid. During administering, the sterilepowder or the sterile liquid of the first part-cylinder mixes with theliquid of the second part-and cylinder by way of a bypass in the firstpart-cylinder, on the needle side. The part-cylinder on the plunger sideis closed at the distal end by a plug and at the proximal end by aplunger. The two part-cylinders are connected to each other by adhesionor welding by means of flanges or by means of a further (over)cylinder,the inside diameter of which corresponds to the outside diameter of thetwo part-cylinders.

The prior-art syringe systems have the disadvantage that they are notsuitable for insertion into an application system (for example into apen system) and/or the solid component first has to be lyophilized inthe part-cylinder on the needle side in order to obtain a solid,powdered component. Moreover, no solution compensating for the pressureproduced when the two part-cylinders are joined together is mentioned inthe prior art.

SUMMARY

The object of the present invention is therefore to provide an improvedand more cost-effective method for producing two-chamber carpules andfor filling two-chamber carpules.

The present invention relates to a two-chamber carpule comprising

-   -   a) a first part-cylinder (1) on the head side, which forms a        chamber, containing a bypass (3),    -    an opening for receiving an intermediate plug (6) at the        proximal end (4), and an intermediate plug (6) in the opening of        the proximal end,    -   b) a liquid- and gas-tight closure (5) at the end on the head        side of the first part-cylinder (1) on the head side,    -   c) a second part-cylinder (2) on the head side, which forms a        second portion of the two-chamber carpule assigned to the second        chamber, containing    -    an opening at the distal end (8),    -    an opening (9) for receiving an end plug (10) at the end on the        plunger side, and an end plug (10) in the opening of the end on        the plunger side of the second part-cylinder, optionally a        second intermediate plug (17) at the distal end,    -   d) optionally a sealing element (7) between the first        part-cylinder and the second part-cylinder.

The proximal end of the first part-cylinder and the distal end of thesecond part-cylinder are connected to each other in a sealed manner.

The invention also relates to the head of a two-chamber carpule asdescribed above, containing

-   -   a bypass (3),    -   an opening for receiving an intermediate plug (6) at the        proximal end (4),    -   a liquid-tight closure cap (5) at the distal end for piercing        with an application needle, and    -   an intermediate plug (6) in the opening of the proximal end.

The front chamber, which is formed in the first part-cylinder in theassembled state, contains a solid or liquid component. Preferably, thechamber contains a solid component, with particular preference alyophilizate or powder. The rear chamber, which is formed in the secondpart-cylinder in the assembled state, contains a liquid component. Thesolid or liquid component of the front chamber and the liquid componentof the rear chamber form the medicament to be administered.

The medicament contains one or more pharmaceutically active ingredientsselected from the group comprising (i) a low molecular weight compound(with a molecular weight of up to 1500 Da), (ii) a peptide, (iii) aprotein, (iv) DNA, (v) RNA, (vi) an antibody, (vii) an enzyme and (viii)an oligonucleotide,

-   -   preferably containing at least one peptide, with preference a        peptide for the treatment of Diabetes mellitus or complications        of Diabetes mellitus such as for example diabetic retinopathy,    -   with particular preference selected from the group comprising        human insulin, a human insulin analog, a human insulin        derivative, glucagon-like peptide-1 (GLP1), a GLP1 analog, a        GLP1 derivative, exendin-3, exendin-4, an exendin-3 analog, an        exendin-4 analog, an exendin-3 derivative or an exendin-4        derivative.

Insulin analogs are, for example, Gly(A21), Arg(B31), Arg(B32) humaninsulin; Lys (B3), Glu(B29) human insulin; Lys (B28), Pro (B29) humaninsulin; Asp (B28) human insulin; human insulin in which proline in theposition B28 has been substituted by Asp, Lys, Leu, Val or Ala and whereLys in position B29 can be substituted by Pro; Ala (B26) human insulin;des(B28-B30) human insulin; des(B27) human insulin and des(B30) humaninsulin.

Insulin derivatives are, for example, B29-N-myristoyl-des(B30) humaninsulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl humaninsulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin;B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30 human insulin; B29-N-(N-palmitoyl-Y-glutamyl)-des(B30)human insulin; B29-N-(N-lithocholyl-Y-glutamyl)-des(B30) human insulin;B29-N-(w-carboxyheptadecanoyl)-des(B30) human insulin andB29-N-(w-carboxyheptadecanoyl) human insulin.

Exendin-4 preferably means exendin-4(1-39), a peptide with the sequenceH-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH₂.

Exendin-4 derivatives are, for example, selected from the followinggroup of compounds:

-   H-(Lys)₄-des Pro³⁶, des Pro³⁷ exendin-4(1-39)-NH₂,-   H-(Lys)₅-des Pro³⁶, des Pro³⁷ exendin-4(1-39)-NH₂,-   des Pro³⁶ [Asp²⁸] exendin-4(1-39),-   des Pro³⁶ [IsoAsp²⁸] exendin-4(1-39),-   des Pro³⁶ [Met(O)¹⁴, Asp²⁸] exendin-4(1-39),-   des Pro³⁶ [Met(O)¹⁴, IsoAsp²⁸] exendin-4(1-39),-   des Pro³⁶ [Trp(O₂)²⁵, Asp²⁸] exendin-4(1-39),-   des Pro³⁶ [Trp(O₂)²⁵, IsoAsp²⁸] exendin-4(1-39),-   des Pro³⁶ [Met(O)¹⁴ Trp(O₂)²⁵, Asp²⁸] exendin-4(1-39),-   des Pro³⁶ [Met(O)¹⁴ Trp(O₂)²⁵, IsoAsp²⁸] exendin-4(1-39); or-   des Pro³⁶ [Asp²⁸] exendin-4(1-39),-   des Pro³⁶ [IsoAsp²⁸] exendin-4(1-39),-   des Pro³⁶ [Met(O)¹⁴, Asp²⁸] exendin-4(1-39),-   des Pro³⁶ [Met(O)¹⁴, IsoAsp²⁸] exendin-4(1-39),-   des Pro³⁶ [Trp(O₂)²⁵, Asp²⁸] exendin-4(1-39),-   des Pro³⁶ [Trp(O₂)²⁵, IsoAsp²⁸] Exendin-4(1-39),-   des Pro³⁶ [Met(O)¹⁴ Trp(O₂)²⁵, Asp²⁸] exendin-4(1-39),-   des Pro³⁶ [Met(O)¹⁴ Trp(O₂)²⁵, IsoAsp²⁸] exendin-4(1-39), the group    -Lys₆-NH₂ being linked with the C-terminus of the exendin-4    derivative; or    an exendin-4 derivative of the sequence-   H-(Lys)₆-des Pro³⁶ [Asp²⁸] exendin-4(1-39)-Lys₆-NH₂,-   des Asp²⁸ Pro³⁶, Pro³⁷, Pro38exendin-4(1-39)-NH₂,-   H-(Lys)₆-des Pro³⁶, Pro³⁸ [Asp²⁸] exendin-4(1-39)-NH₂,-   H-Asn-(Glu)₅des Pro³⁶, Pro³⁷, Pro³⁸ [Asp²⁸] exendin-4(1-39)-NH₂,-   des Pro³⁶, Pro³⁷, Pro³⁸ [Asp²⁸] exendin-4(1-39)-(Lys)₆-NH₂,-   H-(Lys)₆-des Pro³⁶, Pro³⁷, Pro³⁸ [Asp²⁸] exendin-4(1-39)-(Lys)₆-NH₂,-   H-Asn-(Glu)₅-des Pro³⁶, Pro³⁷, Pro³⁸ [Asp²⁸]    exendin-4(1-39)-(Lys)₆-NH₂,-   H-(Lys)₆-des Pro³⁶ [Trp(O₂)²⁵, Asp²⁸] exendin-4(1-39)-Lys₆-NH₂,-   H-des Asp²⁸ Pro³⁶, Pro³⁷, Pro³⁸ [Trp(O₂)²⁵] exendin-4(1-39)-NH₂,-   H-(Lys)₆-des Pro³⁶, Pro³⁷, Pro³⁸ [Trp(O₂)²⁵, Asp²⁸]    exendin-4(1-39)-NH₂,-   H-Asn-(Glu)₅-des Pro³⁶, Pro³⁷, Pro³⁸ [Trp(O₂)²⁵, Asp²⁸]    exendin-4(1-39)-NH₂,-   des Pro³⁶, Pro³⁷, Pro³⁸ [Trp(O₂)²⁵, Asp²⁸]    exendin-4(1-39)-(Lys)₆-NH₂,-   H-(Lys)₆-des Pro³⁶, Pro³⁷, Pro³⁸ [Trp(O₂)²⁵, Asp²⁸]    exendin-4(1-39)-(Lys)₆-NH₂,-   H-Asn-(Glu)₅-des Pro³⁶, Pro³⁷, Pro³⁸ [Trp(O₂)²⁵, Asp²⁸]    exendin-4(1-39)-(Lys)₆-NH₂,-   H-(Lys)₆-des Pro³⁶ [Met(O)¹⁴, Asp²⁸] exendin-4(1-39)-Lys₆-NH₂,-   des Met(O)¹⁴ Asp²⁸ Pro³⁶, Pro³⁷, Pro³⁸ exendin-4(1-39)-NH₂,-   H-(Lys)₆-desPro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Asp²⁸]    exendin-4(1-39)-NH₂,-   H-Asn-(Glu)₅-des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Asp²⁸]    exendin-4(1-39)-NH₂,-   des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Asp²⁸]    exendin-4(1-39)-(Lys)₆-NH₂,-   H-(Lys)₆-des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Asp²⁸]    exendin-4(1-39)-(Lys)₆-NH₂,-   H-Asn-(Glu)₅ des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Asp²⁸]    exendin-4(1-39)-(Lys)₆-NH₂,-   H-Lys₆-des Pro³⁶ [Met(O)¹⁴, Trp(O₂)²⁵, Asp²⁸]    exendin-4(1-39)-Lys₆-NH₂,-   H-des Asp²⁸ Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Trp(O₂)²⁵]    exendin-4(1-39)-NH₂,-   H-(Lys)₆-des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Asp²⁸]    exendin-4(1-39)-NH₂,-   H-Asn-(Glu)₅-des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Trp(O₂)²⁵, Asp²⁸]    exendin-4(1-39)-NH₂,-   des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Trp(O₂)²⁵, Asp²⁸]    exendin-4(1-39)-(Lys)₆-NH₂,-   H-(Lys)₆-des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Trp(O₂)²⁵, Asp²⁸]    exendin-4(S1-39)-(Lys)₆-NH₂,-   H-Asn-(Glu)₅-des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Trp(O₂)²⁵, Asp²⁸]    exendin-4(1-39)-(Lys)₆-NH₂;    or a pharmaceutically acceptable salt or solvate of exendin-4 or of    one of the aforementioned exendin-4 derivatives.

The pharmaceutically active ingredient is preferably the solid componentin the chamber of the front part-cylinder, with particular preference alyophilizate or a powder.

Pharmaceutically acceptable salts are, for example, acid addition saltsand basic salts. Acid addition salts are, for example, HCl or HBraddition salts. Basic salts are, for example, salts in which the cationis selected from the group of alkali salts, for example Na⁺ or K⁺, orthe earth alkali salts, for example Ca²⁺, or ammonia ionsN⁺(R₁)(R₂)(R₃)(R₄), where R₁ to R₄ mean, independently of one another:hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₆-C₁₀-aryl, or C₆-C₁₀-heteroaryl.Further examples of pharmaceutically acceptable salts are described in“Remington's Pharmaceutical Sciences” 17. Ed. Alfonso R. Gennaro (Ed.),Mark Publishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopediaof Pharmaceutical Technology.

In a preferred embodiment, either the proximal end (4) of the firstpart-cylinder, on the head side, or the distal end (8) of the secondpart-cylinder, on the plunger side, contains an axial groove (11) on theinner side of the receiving part-cylinder. When the two part-cylinders(1) and (2) are joined together, pressures which could press out the endplug (10) can build up in the hollow space of the part-cylinder (2). Thepressure can be substantially avoided by the axial groove (11), since itcan initially escape during joining together. The groove is formed insuch a way that it has a length axially that is smaller than the lengthof the engagement of the proximal end of the one part-cylinder in thecorresponding end of the other part-cylinder. Furthermore, the groove isformed in such a way that it further reduces the wall thickness of thereceiving part-cylinder. If, for example, as represented in FIG. 1 a,the proximal end (4) of the first part-cylinder, on the head side,engages in the distal end (8) of the second part-cylinder, on theplunger side, the pressure that is built up during joining together caninitially escape through the groove (11). Only in the final assemblystep is it no longer possible for the pressure to escape by way of thegroove, but the pressure is so low that it can longer press out the endplug (10). In a particularly preferred embodiment, the part-cylinders(1) and (2), one of which contains an axial groove, are connected toeach other by means of clamping closure.

In a further preferred embodiment, the proximal end (9) of the secondpart-cylinder, on the plunger side, has a stop (13). The stop preventsslipping of the end plug (10) being caused by the pressure in thedirection of the proximal end produced during joining together. The stopis formed in such a way that the plunger can transfer force to the endplug through the proximal opening of the second part-cylinder.

In a further preferred embodiment, the distal end (8) of the secondpart-cylinder, on the plunger side, has a plug (17).

In a particularly preferred embodiment, the two-chamber carpule containsboth an axial groove (11) in the receiving part-cylinder and a stop (13)at the proximal end (9) of the second part-cylinder, on the plungerside.

In an especially preferred embodiment, the two-chamber carpule containsan axial groove (11) in the receiving part of the cylinder, and a stop(13) at the proximal end (9) of the second part-cylinder, on the plungerside, and a plug at the distal end (8) of the second part-cylinder, onthe plunger side.

“Proximal” means the end of a component that is facing the end plug (10)in the assembled state, that is to say facing the plunger and the thumbof the person administering the preparation when the two-chamber carpuleis installed in a pen system and a plunger of the application systemacting on the end plug (10) is actuated by the thumb of the personadministering the preparation. The proximal end of the firstpart-cylinder is the end of the part cylinder that is connected to thesecond part-cylinder in the assembled state.

“Distal” means the end of a component that is facing the closure (5) orthe outlet opening in the assembled state. For example, the distal endof the second part-cylinder is the end of the part of the cylinder thatis connected to the first part-cylinder in the assembled state.

The “end on the head side of the two-chamber carpule” is the end of thetwo-chamber carpule that forms the head of the two-chamber carpule, thatis to say comprises the closure (5) or the outlet opening.

The “end on the plunger side of the two-chamber carpule” is the end ofthe two-chamber carpule that comprises the end plug (10) and at which orby which the force of the plunger is transferred in a pen system.

The closure cap (5) is a device which closes the distal end of thepart-cylinder (1) in a liquid- and gas-tight manner. The cap comprises asealing element (15), for example a cartridge-like disk, and a closureelement (16), for example made of aluminum or plastic, which bringsabout the permanent connection and the sealing force between the sealingelement (15) and the part-cylinder (1). The connection may beestablished by methods known to a person skilled in the art, for exampleby crimping, flanging, pressing or screwing.

The plugs (6) (10) and (17) and the sealing element (7), independentlyof one another, are made of elastic material, for example rubber,preferably brominated butyl rubber, chlorinated butyl rubber orfluorinated butyl rubber. Optionally, the plugs are coated with PTFE.The plugs are preferably of a cylindrical basic form, but other basicforms corresponding to the inner form of the part-cylinders are alsopossible. The plugs have both a sealing function and a closing function,for example intermediate plug (6) closes and seals the proximal end (4)of the first part-cylinder. The sealing function is preferably ensuredby one or more lamellar formations of the cylindrical basic form.

“Sealed” means impermeability with respect to solids, liquids, gases andwith respect to germs.

The bypass (3) is an opening which makes it possible when thetwo-chamber carpule is being used for a liquid component (14) to flowout of part-cylinder (2) into part-cylinder (1), bypassing theintermediate plug (6) or the intermediate plugs (6) and (17), while themedicament is administered. The bypass (3) can be created by one or morechannels, which are located in the material of the wall of thepart-cylinder (1), i.e. are let into or worked into the material of thewall. By appropriate forming of the material of the wall, the bypass mayalso be formed inward (depression running along the inner wall, notdepicted) or outward (elevation widening the outer diameter, as depictedfor example in FIG. 1). The arrangement may be configured axially orradially deviating from the axial direction.

The part-cylinders (1) and (2) are formed independently of each otherfrom glass, plastic, metal or other materials, with preferencetransparent materials such as glass or plastic. Preferred plastics arepolycarbonate, polyesters, cycloolefin copolymers (COC) or cycloolefinpolymers (COP).

The first part-cylinder (1), on the head side, and the secondpart-cylinder (2), on the plunger side, are positively and/ornonpositively connected to each other in a way known to a person skilledin the art, for example by screw closure, plug-in closure, bayonetclosure, snap-in closure or clamping closure (represented in thefigures). Depending on the choice of materials, the connection is withpreference self-sealing, or is for example accomplished by adhesion orwelding. A sealing element (7) may optionally be used.

In one embodiment, the first part-cylinder (1), on the head side, is thereceiving component. If the first part-cylinder (1), on the head side,and the second part-cylinder (2), on the plunger side, are connected toeach other for example by screw closure, the first part-cylinder (1), onthe head side, has an internal thread at the distal end, and the secondpart-cylinder (2), on the plunger side, has a corresponding externalthread at the proximal end.

In a further embodiment, the second part-cylinder (2), on the plungerside, is the receiving component. If the second part-cylinder (2), onthe plunger side, and the first part-cylinder (1), on the head side, areconnected to each other for example by screw closure, the secondpart-cylinder (2), on the plunger side has an internal thread at theproximal end, and the first part-cylinder (1), on the head side, has acorresponding external thread at the distal end.

In general, a combination of all the stated general and preferredfeatures of the embodiments is technically possible.

In a further preferred embodiment, both part-cylinders (1) and (2)consist of plastic. In a particularly preferred embodiment, the twoplastic part-cylinders are connected to each other by means of a screwclosure, a sealing element optionally being inserted between thepart-cylinders for sealing purposes. It is especially preferred in thisembodiment for the distal end (8) of the second cylinder, on the headside, to contain an axial groove (11), by way of which the pressurebuilt up in the part-cylinder (2) during the assembly of the twopart-cylinders can escape; alternatively, the end plug (10) may bepositioned in the part-cylinder (2) in such a way that, during assembly,it is displaced into the desired end position by the built-up pressure.With preference, the second part-cylinder (2) contains a plug (17) atthe distal end. Optionally, the part-cylinder (2) contains a stop (13)at the proximal end.

In a further preferred embodiment, the first part-cylinder (1) consistsof glass and the second part-cylinder(2) consists of plastic, whichpart-cylinders are connected to each other with particular preference bymeans of a clamping closure or a plug-in closure. The sealing of thepart-cylinders may take place by adhesion by means of conventionalpharmaceutically acceptable adhesive, a sealing element optionally beinginserted between the part-cylinders. It is especially preferred in thisembodiment for the distal end (8) of the second cylinder, on the headside, to contain an axial groove (11), by way of which the pressurebuilt up in the part-cylinder (2) during the assembly of the twopart-cylinders can escape; alternatively, the end plug (10) may bepositioned in the part-cylinder (2) in such a way that, during assembly,it is displaced into the desired end position by the built-up pressure.With preference, the second part-cylinder (2) contains a plug (17) atthe distal end. Optionally, the part-cylinder (2) contains a stop (13)at the proximal end.

In a further preferred embodiment, both part-cylinders (1) and (2)consist of plastic, and the part-cylinders are connected to each otherby way of a plug-in closure, a sealing element optionally being insertedbetween the part-cylinders for sealing purposes. It is especiallypreferred in this embodiment for the distal end (8) of the secondpart-cylinder, on the plunger side, to contain an axial groove (11), byway of which the pressure built up in the part-cylinder (2) during theassembly of the two part-cylinders can escape; alternatively, the endplug (10) may be positioned in the part-cylinder (2) in such a way that,during assembly, it is displaced into the desired end position by thebuilt-up pressure. With preference, the second part-cylinder (2)contains a plug (17) at the distal end. Optionally, the part-cylinder(2) contains a stop (13) at the proximal end.

It is common to all the embodiments that the liquid component (14) andthe solid component (12) are filled with preference under sterileconditions.

The two-chamber carpule according to the invention has the advantagethat the two part-cylinders can be filled separately from each otherthrough the entire diameter of the part-cylinders, and that the firstpart-cylinder (1), on the head side, and, if the plug (17) is present,also a second part-cylinder (2), on the plunger side, can be producedseparately from each other, and consequently can be kept in storage. Thesecond intermediate plug (17) also has the effect that there is no riskof contamination by the solid or liquid component at the points ofcontact between the first and second part-cylinders. The filling by wayof large openings ensures a reduced likelihood of contamination of theother part-cylinder respectively, or the outside of the carpule. Sincepowder can be filled directly, lyophilizing is not necessary. Instead, alyophilizate or some other solid component, preferably in powder form,can be filled in directly. The innocuous filling with powder alsoensures that no influencing of the crystalline structure of the powdercan occur by way of shearing forces, such as those which can occurduring filling through small openings, and so influencing of thebiocompatibility of the medicaments to be administered is not to beexpected.

The two-chamber carpule according to the invention can be used in anyapplication system, for example a pen system, the application systempreferably including a needle for piercing a distal sealing disk (15),and a drive mechanism for moving the end plug (10) in the distaldirection.

The carpule is also distinguished by outstanding cost-effectiveness,since the rapidity of filling and possibly adaptation of the rate offilling of the part-cylinder on the head side to that of the filling ofthe part-cylinder on the plunger side makes the method for producing andfilling the carpule advantageous.

Preferably, the two part-cylinders are injection-molded under clean-roomconditions, then sterilized while hermetically packed.

The use of plastic as the material for the part-cylinders additionallyensures low-cost production of the parts, the integration of functionalparts required for operating a pen system on one of the part-cylinders(synergies), a simple process to establish freedom from particles,sterilization, depyrogenization, high dimensional stability andrecyclability.

The invention also relates to an applicator including a two-chambercarpule as described above.

The invention also relates to a method for producing and fillingtwo-chamber carpules, wherein

-   -   a) a first part-cylinder (1), on the head side, is closed with a        liquid- and gas-tight closure cap (5) at the end on the head        side;    -   b) the chamber of the first part of the cylinder (1), on the        head side, is preferably filled with solid component (12), with        particular preference a powder, and closed by means of an        intermediate plug (6);    -   c) a second part cylinder (2), on the plunger side, is closed at        the proximal end with an end plug (10);    -   d) the chamber of a second part-cylinder (2), on the plunger        side, is filled with a liquid component (14) and optionally        closed with an additional intermediate plug (17); and    -   e) the two-part cylinders (1) and (2) are joined together, a        sealing element (7) optionally being inserted between the first        and second part-cylinders.

The components of the two-chamber carpule are as defined above in theirgeneral and preferred embodiments.

Alternatively, the first four steps may also be carried out in thesequence c), d), a), b).

In a preferred embodiment, the end plug (10) is positioned before thejoining together of the two part-cylinders (1) and (2) in such a waythat the built-up pressure displaces the plug (10) into the desired endposition. The end plug (10) can in principle be introduced from bothends of the part-cylinder (2); with preference, the end plug (10) isintroduced by way of the proximal end.

In a further preferred embodiment, the part-cylinders are assembledunder vacuum conditions. Displacement of the end plug (10) issubstantially avoided by this measure.

A person skilled in the art has at his disposal a series of knownpossible ways of joining together the two part-cylinders.Material-bonding (welding), nonpositively (adhesion) or positively(snap-in closure) engaging connecting techniques may be used, theirsuitability depending on the materials that are respectively used forthe part-cylinders of the syringe. If both part-cylinders are made ofplastic, a welded connection comes into consideration in particular;however, adhesion is also possible, a connecting technique that can alsobe used if both part-cylinders consist of glass. In a furtherrefinement, the two cylinder parts, irrespective of whether they areproduced from glass or plastic, may be connected to each other by meansof a sealing snap-in connection or include a sealing element (7).

Further refinements and advantages of the invention emerge from thefollowing description of the exemplary embodiments that are representedin the drawings.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 a shows the basic construction of the two-chamber carpuleaccording to the invention as an exploded drawing. FIG. 1 b shows theconstruction of the carpule in the assembled state. FIG. 1 c shows theconstruction of the closure cap (5).

FIG. 2 a shows the carpule according to the invention in comparison witha conventional two-chamber carpule in FIG. 2 b.

FIG. 3 a and FIG. 3 b shows the work being performed on thepart-cylinder (2) when adding the end plug (10) and the liquid component(14). FIG. 3 c shows the part-cylinder (2) being closed in a sterilemanner by the fitting of an additional plug (17).

FIGS. 4 a to 4 d show the production and filling of the firstpart-cylinder (1), first the closure (5) being placed on the proximalend, a dry active preparation (12) subsequently filled in, and theintermediate plug (6) fitted.

FIG. 5 a represents the joining together of the two part-cylinders (1)and (2) filled with liquid carrier medium and dry active preparation.FIG. 5 b shows the ready-to-use, assembled two-chamber carpule.

DETAILED DESCRIPTION

One possible assembly procedure of the two-chamber carpule is describedbelow (FIGS. 3-5):

1. Placing of the plug (10) into the part-cylinder (2). The end plug(10) can be introduced from both ends of the part-cylinder (2), thepreferred end being the proximal end (FIG. 3 a).

2. When the end plug (10) has been brought into its position, thepart-cylinder (2) is filled with liquid carrier medium (14) (FIG. 3 b).The length of the part-cylinder (2) is dictated by the volume of thecarrier medium (14) to be filled in. Optionally, the part-cylinder (2)may be closed in a sterile manner with a plug (17).

3. The part-cylinder (1) is first closed by placing the closure cap (5)on the end on the head side (FIG. 4 a). If a sealing disk (15) is used,it can be subsequently placed, or the sealing disk may be fitted onbefore the closure cap (5) is placed on.

4. The part-cylinder (1) is filled with a dry active preparation (12)(FIG. 4 b). 5. The part-cylinder (1) on the head side is closed with theplug (6) (FIG. 4 c; FIG. 4 d shows the filled and closed part-cylinder(1)).

6. To complete the ready-to use two-chamber carpule, the part-cylinder(1) is pushed into the opening at the distal end (8) of thepart-cylinder (2) (FIG. 5 a), i.e. the part-cylinder (2) is closed bythe first part-cylinder (1) (FIG. 5 b).

1-15. (canceled)
 16. A two-chamber carpule for use with an applicationsystem comprising: a) a first part-cylinder having a proximal end and adistal end, the first part-cylinder forming a first chamber comprising,a needle pierceable closure at the distal end, a bypass, an opening forreceiving an intermediate plug at the proximal end, and an intermediateplug slidably positioned in the opening of the proximal end; and b) asecond part-cylinder having a proximal end and a distal end, the secondpart-cylinder forming a second chamber comprising, an opening at thedistal end, an opening for receiving an end plug at the proximal end,and an end plug slidably positioned in the opening of the proximal end;wherein one or both of the proximal end of the first part cylinder andthe distal end of the second part-cylinder are configured to preventpressure build-up in the second chamber when the first part-cylinder andthe second part-cylinder are joined together during assembly, where theresulting assembly is configured to be inserted and installed into anapplication system.
 17. The two-chamber carpule of claim 16 where thefirst chamber contains a solid and the second chamber contains a liquid.18. The two-chamber carpule of claim 16 where the first chamber containsa liquid and the second chamber contains a liquid.
 19. The two-chambercarpule of claim 16 where a sealing element is positioned between thefirst part-cylinder and the second part cylinder.
 20. The two-chambercarpule of claim 16 where the proximal end of the first part-cylinderand the distal end of the second part-cylinder are configured to form aclosure selected from the group consisting of a screw, adhesive, snapand a combination of such closures.
 21. The two-chamber carpule of claim20 where the first part-cylinder and the second part-cylinder arecomprised of plastic.
 22. The two-chamber carpule of claim 16 where theproximal end of the second part-cylinder has a stop.
 23. An applicationsystem to deliver medicament comprising, a. the two-chamber carpule ofclaim 1; and b. a drive mechanism for moving the end plug in the distaldirection.